Calcium ions play a central role in the control of neurotransmitter release and synaptic transmission in most systems. The pioneering work of Katz and Miledi on the neuromuscular junction demonstrated that calcium ions must be present at the line of presynaptic depolarization if transmitter release is to occur and that the size of the postsynaptic potential (a measure of the quantity of neurotransmitter released) is a function of the amount of calcium entering presynaptically through voltage-dependent channels. Developments in past several years suggest that certain of their conclusions, however, may not be universally applicable to all synapses. Transmission at some synapses between central neurons, for example, is thought to be calcium-independent. At others, transmitter release may not be quantal. These observations suggest that there may be more than one mechanism responsible for the release of transmitter, an idea that is supported by recent evidence that secretion of peptides may differ fundamentally from secretion of classical neurotransmitters. Furthermore, it has become clear that several different calcium channel types exist, raising questions as to which calcium channel regulates exocytosis, and whether different types of calcium channel might be coupled to the release of different types of transmitter. Dorsal root ganglion neurons in vitro constitute an ideal preparation in which to investigate these questions because they exhibit at least three types of voltage-dependent calcium channel and synthesize, store, and release both peptides and classical transmitters. Using biochemical, electrophysiological, and pharmacological techniques we will compare several aspects of the release mechanisms for substance P and glutamate in dissociated cultures of dorsal root ganglion neurons. The results are likely to provide significant insights into the mechanisms underlying the communication between neurons and their targets.